Calcineurin Inhibitor Nephrotoxicity Research Articles

Randomized Sirolimus-based Early Calcineurin Inhibitor Reduction in Liver Transplantation: Impact on Renal Function.

The long-term use of calcineurin inhibitors (CNIs) after liver transplantation (LT) is associated with nephrotoxicity. Five-year follow-up data were retrieved from the randomized controlled multicenter SiLVER trial. Standard CNI-based mammalian target of rapamycin-free immunosuppression (group A, n = 264) was compared with a 50% reduction of CNI and introduction of the mammalian target of rapamycin inhibitor Sirolimus (SIR) within 4-6 weeks after LT (group B, n = 261). Median MELD at LT was low with 10 (7-15) (group A) and 11 (8-15) (group B) in the intention-to-treat approach. CNI dose and CNI trough were reduced by 20% and 8% (group A) versus 55% and 56% (group B) at 3 months posttransplantation. Renal function was preserved at 3 months after LT in the SIR arm (estimated glomerular filtration rate 74 [57-95] versus 67 [55-85] mL/min/1.73m2 P = 0.004) but was similarly impaired thereafter compared with group A. The per protocol analysis identified LT recipients in group B with concomitant early CNI minimization and SIR treatment ≥ year 1 with significantly superior estimated glomerular filtration rate and lowest rate of chronic kidney disease (≥stage 3) from year 1 onwards until study end. Competing risk factors for renal disease (arterial hypertension, fat metabolism disorder, and hyperglycemia) were not associated with worse kidney function. Prevention of CNI nephrotoxicity by SIR-based early CNI minimization protects renal function only short-term after LT in the intention-to-treat analysis of this low MELD cohort. Yet, selected LT recipients compliant with early CNI minimization and SIR maintenance achieved better long-term renal outcomes compared with real-world practice.

Lack of Relationship Between Renal Function and Genetic Variants of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT1A8, and UGT2B7 in Patients After Liver Transplantation in a 2-Year Follow-up

BackgroundThe prolonged survival time after liver transplantation (LTX) creates the possibility of the occurrence and development of complications in the late post-transplantation period. Deterioration of renal function is 1 of these complications. The nephrotoxicity of calcineurin inhibitors (CNIs) and their metabolites produced during pharmacokinetic processes in the body is also postulated. The study was aimed at assessment of the relationship between selected single gene polymorphisms (SNPs) for enzymes and transport proteins and change of estimated glomerular filtration rate (ΔeGFR) during 2-year follow-up in LTX patients. MethodsThe study involved 244 patients after LTX (105 women [43.0%] and 139 men [57.0%]) receiving tacrolimus (191; 78.3%) or cyclosporine A (53; 21.7%). The study protocol conforms with the Declaration of Helsinki. ResultsWe have not observed significant differences of ΔeGFR between groups distinguished based on analyzed genotypes in patients treated with cyclosporine or tacrolimus. ConclusionGenetic variations of CYP3A4, CYP3A5, MDR1, MRP2, UGT1A9, UGT2B7, and UGT2B7 tested in LTX recipients are not associated with kidney function during the 24-month follow-up.

Impact of donor-related arteriosclerosis in pretransplant biopsy on long-term outcome of living-kidney transplantation: A propensity score-matched cohort study.

To compare the long-term outcome and complications of living-kidney grafts with arteriosclerosis to those without abnormal findings diagnosed using pretransplant graft biopsy, and to assess the impact of the arteriosclerosis in living-donor kidneys. The influence of arteriosclerosis in pretransplant biopsy on long-term outcomes and complications was evaluated in both unmatched (n=1351, without arteriosclerosis n=788 vs with arteriosclerosis n=563) and propensity score-matched cohorts (n=984, without arteriosclerosis n=492 vs with arteriosclerosis n=492) of adults who underwent living-kidney transplant. In both the unmatched and matched cohort, there was no significant difference in patient and death-censored graft survival at 10years between the without arteriosclerosis and with arteriosclerosis groups. The with arteriosclerosis group had a higher incidence rate of overall rejection than did the without arteriosclerosis group in both the unmatched (P=0.026) and matched (P=0.060) cohorts. The with arteriosclerosis group had significantly higher chronic antibody-mediated rejection than did the without arteriosclerosis group (P=0.006) in the unmatched cohort. The with arteriosclerosis group had a significantly lower estimated glomerular filtration rate in recipients, but there was no significant difference after matching. The incidence rates of calcineurin inhibitor nephrotoxicity and post-transplant anemia were significantly higher in the with arteriosclerosis group than in the without arteriosclerosis group in both the unmatched and matched cohorts. Long-term postoperative kidney function of living donors was lower in the with arteriosclerosis group. Kidney graft with arteriosclerosis might affect the incidence of rejection, complications and postoperative kidney function of donors. Long-term careful observation is required for both the recipients who received grafts with arteriosclerosis and the donors who had kidneys with arteriosclerosis.

Combined Heart-Kidney Transplant Versus Sequential Kidney Transplant in Heart Transplant Recipients

In patients with reduced kidney function there are no established guidelines to suggest combined heart-kidney transplant (HKTx) versus sequential kidney transplant (SKTx) using preoperative value of estimated glomerular filtration (eGFR). The United Network for Organ Sharing database was queried from 2000 to 2015 to evaluate survival of HKTx and SKTx population stratified by preoperative eGFR rate <45 mL/min. Aim of the study was to assess the eGFR rate that is most beneficial to perform a concomitant or a SKTx at time of transplant evaluation. In our analysis, patients who required SKTx are recipients that, after heart transplantation, developed or worsened kidney insufficiency due to calcineurin inhibitor nephrotoxicity. In recipients with eGFR <30 or dialysis, a total of 545 received HKTx and 80 received SKTx. The median waiting time between heart and kidney transplant in SKTx group was 6 years. The overall post-transplant survival was 81% and 80% and 75% and 59% at 5 and 1 years for the HKTx and SKTx groups, respectively (P = .04). In recipients with eGFR from 30 to 44, a total of 107 received HKTx and 112 received SKTx. The median waiting time between heart and kidney transplant in SKTx group was 4 years. Overall post-transplant survival showed no statistically significant differences in HKTx group (n=107) compared with SKTx group (n=112) and was 90% and 95% at 1 year and 74% and 52% at 5 years, respectively (P = .4) . To optimize organ and patient survival, eGFR value can be utilized to discern between HKTx versus SKTx in patients with decreased renal function at the time of heart transplantation. Patients with eGFR<30 or in dialysis presented better survival with HKTx, while both SKTx and HKTx are suitable for patients with eGFR between 30 and 45.

Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor–Related Nephrotoxicity

BackgroundThere is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. MethodsData from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. ResultsIn 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. ConclusionsA therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.

De Novo Belatacept in a Kidney-After-Heart Transplant Recipient.

Renal injury almost always accompanies the multisystem organ failure that precedes cardiac transplantation and renal function is further compromised by the nephrotoxicity of calcineurin inhibitors posttransplant. Renal dysfunction in turn causes significant morbidity and mortality. The development of belatacept was motivated by need for an alternative to calcineurin-based immunosuppression, particularly in renal transplantation where the nephrotoxicity of calcineurin inhibitors reduce graft longevity and adverse cardiovascular effects of calcineurin inhibitors increase overall mortality. In 2011, the FDA approved belatacept for use in renal transplantation. Seven-year data from the multicenter randomized phase III BENEFIT trial, which compared belatacept with cyclosporine in renal transplant recipients, show belatacept therapy offers both improved renal function and 43% risk reduction for the combined endpoint of graft loss and death. At present, belatacept use is predominantly confined to renal transplant recipients; however, reports of belatacept use in other transplant settings are emerging. Here, we describe successful long-term use of belatacept in a kidney-after-heart transplant recipient and review use of belatacept in cardiothoracic and other nonrenal transplant settings.

The Many Faces of Calcineurin Inhibitor Toxicity-What the FK?

Calcineurin inhibitors (CNIs) are both the savior and Achilles' heel of kidney transplantation. Although CNIs have significantly reduced rates of acute rejection, their numerous toxicities can plague kidney transplant recipients. By 10years, virtually all allografts will have evidence of CNI nephrotoxicity. CNIs have been strongly associated with hypertension, dyslipidemia, and new onset of diabetes after transplantation-significantly contributing to cardiovascular risk in the kidney transplant recipient. Multiple electrolyte derangements including hyperkalemia, hypomagnesemia, hypercalciuria, metabolic acidosis, and hyperuricemia may be challenging to manage for the clinician. Finally, CNI-associated tremor, gingival hyperplasia, and defects in hair growth can have a significant impact on the transplant recipient's quality of life. In this review, the authors briefly discuss the pharmacokinetics of CNI and discuss the numerous clinically relevant toxicities of commonly used CNIs, cyclosporine and tacrolimus.

Chronic interstitial nephritis in agricultural communities is a toxin-induced proximal tubular nephropathy

Almost 30 years after the detection of chronic interstitial nephritis in agricultural communities (CINAC) its etiology remains unknown. To help define this we examined 34 renal biopsies from Sri Lanka, El Salvador, India and France of patients with chronic kidney disease 2-3 and diagnosed with CINAC by light and electron microscopy. In addition to known histopathology, we identified a unique constellation of proximal tubular cell findings including large dysmorphic lysosomes with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound "aggregates". These aggregates associated with varying degrees of cellular/tubular atrophy, apparent cell fragment shedding and no-weak proximal tubular cell proliferative capacity. Identical lysosomal lesions, identifiable by electron microscopy, were observed in 9% of renal transplant implantation biopsies, but were more prevalent in six month (50%) and 12 month (67%) protocol biopsies and in indication biopsies (76%) of calcineurin inhibitor treated transplant patients. The phenotype was also found associated with nephrotoxic drugs (lomustine, clomiphene, lithium, cocaine) and in some patients with light chain tubulopathy, all conditions that can be directly or indirectly linked to calcineurin pathway inhibition or modulation. One hundred biopsies of normal kidneys, drug/toxin induced nephropathies, and overt proteinuric patients of different etiologies to some extent could demonstrate the light microscopic proximal tubular cell changes, but rarely the electron microscopic lysosomal features. Rats treated with the calcineurin inhibitor cyclosporine for four weeks developed similar proximal tubular cell lysosomal alterations, which were absent in a dehydration group. Overall, the finding of an identical proximal tubular cell (lysosomal) lesion in CINAC and calcineurin inhibitor nephrotoxicity in different geographic regions suggests a common paradigm where CINAC patients undergo a tubulotoxic mechanism similar to calcineurin inhibitor nephrotoxicity.

Histopathology of Chronic Kidney Disease after Allogeneic Hematopoietic Cell Transplantation: A Multi-Center Observational Study of Kidney Biopsies

Background Renal dysfunction is a common complication of allogeneic hematopoietic cell transplantation (Allo-HCT) with proven negative impact on early and long-term mortality. The cumulative incidence of chronic kidney disease(CKD) after Allo- HCT varies from 13~60% in adult studies to as high as 62% in children. So far, most knowledge on chronic renal impairment in the context of Allo-HCT is based on clinical and laboratory findings. Causes of CKD are diverse, usually overlapping, and poorly understood. Kidney biopsies are performed in less than 5% patients with CKD, the pathophysiology of idiopathic CKD remains obscure. We conducted a multi-center clinicopathologic study of Allo-HCT patients with CKD to described the histopathologic spectrum of renal manifestations. Methods and Results Between 2005 and 2018, 24 recipients(17 males and 7 females) of Allo-HCT underwent kidney biopsy for either proteinuria or deterioration of kidney function at four centers. The median age was 43.8 (7.2~54.3) years, and the median time from Allo-HCT to kidney biopsy was 17.2(2.0~74.6)months. Evidence for GVHD was found in 20 (83.3%) patients. Among the 24 patients, 10 patients had a large amount of proteinuria (24-hour urine protein &gt; 3.5 g/L), and 12 patients had elevated serum creatinine (Scr &gt;110μmol/l). The most common pathological findings of kidney biopsy were GVHD (n=8), membranous nephropathy (MN, n=5), thrombotic microangiopathy (TMA, n=4), BK virus nephropathy (n=2), and we also found ischemic nephropathy, chronic interstitial nephritis, minimal change disease (MCD), GVHD with TMA, MN with focal segmental glomerular sclerosis (FSGS), MCD with acute tubular injury, BK virus nephropathy combined with calcineurin inhibitor nephrotoxicity in one case. The follow-up data showed 3 died of recurrent malignancy, 6 loss to follow-up , the median follow-up time was 18.3(12.3~120.2)months. Of the 18 patients, 8 (44.4%) had an estimated glomerular filtration rate (eGFR) of less than 60 ml/(min1.73m2), 5 (27.8%) still had moderate proteinuria. Conclusions A wide spectrum of renal pathologic findings can be observed in Allo-HCT patients. Either severe proteinuria or elevated serum creatinine were common presentations in this unique setting, which can be due to GVHD , MN, TMA, BK virus nephropathy , MCD, FSGS, and overlapping lesions. Kidney biopsies are necessary to establish the underlying cause of CKD in Allo-HCT patients. Disclosures No relevant conflicts of interest to declare.

Conversion From Calcineurin Inhibitors to Belatacept in HLA-sensitized Kidney Transplant Recipients With Low-level Donor-specific Antibodies.

Belatacept could be the treatment of choice in renal-transplant recipients with renal dysfunction attributed to calcineurin inhibitor (CNI) nephrotoxicity. Few studies have described its use in patients with donor-specific antibody (DSA). We retrospectively evaluated conversion from CNIs to belatacept in 29 human leukocyte antigen-immunized renal-transplant recipients. Data about acute rejection, DSA, and renal function were collected. These patients were compared with 42 nonimmunized patients treated with belatacept. Patients were converted from CNIs to belatacept a median of 444 days (interquartile range, 85-1200) after transplantation and were followed up after belatacept conversion, for a median of 308 days (interquartile range, 125-511). At conversion, 16 patients had DSA. Nineteen DSA were observed in these 16 patients, of which 11/19 were <1000 mean fluorescence intensity (MFI), 7/19 were between 1000 and 3000 MFI, and one was >3000 MFI. At last follow-up, preexisting DSA had decreased or stabilized. Seven patients still had DSA with a mean MFI of 1298 ± 930 at the last follow-up. No patient developed a de novo DSA in the DSA-positive group. In the nonimmunized group, one patient developed de novo DSA (A24-MFI 970; biopsy for cause did not show biopsy-proven acute rejection or microinflammation score). After belatacept conversion, one antibody-mediated rejection was diagnosed. The mean estimated glomerular filtration rate improved from 31.7 ± 14.2 mL/min/1.73 m to 40.7 ± 12.3 mL/min/1.73 m (P < 0.0001) at 12 months after conversion. We did not find any significant difference between groups in terms of renal function, proteinuria, or biopsy-proven acute rejection. We report on a safe conversion to belatacept in human leukocyte antigen-immunized patients with low DSA levels.

Infrequent tacrolimus-induced nephrotoxicity in French patients with steroid-dependent nephrotic syndrome.

Chronic nephrotoxicity with potentially irreversible lesions is a major concern regarding calcineurin inhibitor (CNI) treatment in children with severe forms of idiopathic nephrotic syndrome (INS). We retrospectively included all children on CNI for steroid-dependent INS with a duration of CNI treatment of more than 1year. Only patients in whom CNI could not be replaced by mycophenolate mofetil were included. All included patients underwent a kidney biopsy. All results were expressed as median and range. Twenty-one children (6 girls) were included. Age at disease onset was 49 (29-66) months and treatment duration on CNI was 30 (20-45) months. Age at kidney biopsy was 108 (78-170) months. Number of relapses was 7 (3-9) since disease onset. Serum creatinine level was transiently and moderately increased in two patients. Kidney biopsy revealed minimal change disease in 20/21 patients and focal segmental glomerulosclerosis in 1/21. Evidence for chronic CNI nephrotoxicity was found in one patient revealed by arteriolar hyalinosis and fibrosis in 50% of glomeruli. CNI-induced chronic nephrotoxicity was infrequent. In patients who require long-term and/or high-dose CNI treatment, kidney biopsies might be useful to exclude chronic CNI-induced lesions.

Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity

Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regimens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower incidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibility factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT.

Selective Costimulation Blockade With Antagonist Anti-CD28 Therapeutics in Transplantation.

Nephrotoxicity of calcineurin inhibitors and uncontrolled effector function of alloreactive T lymphocytes are main drivers of transplant dysfunctions. T lymphocytes either directly damage tissues or indirectly promote inflammation and antibody responses. Beside inhibitors of calcium-dependent pathways and antimetabolites, modulators of T-cell costimulation are elected pharmacological tools to enable interference with immune-mediated transplant dysfunctions. CD28 and CTLA-4 are major costimulatory and coinhibitory cell surface signaling molecules interacting with CD80/86, known to be critically important for immune response of committed T cells and regulation. Initial bench to beside translation, 2 decades ago, resulted in the development of belatacept CTLA-4 fused with an immunoglobulin Fc domain, a biologic inhibiting interaction of both CD28 and CTLA-4 with CD80/86. Despite proven effectiveness in inhibiting alloimmune responses, clinical use of belatacept in kidney transplantation revealed a substantially high incidence of acute, cell-mediated rejection. The cause of belatacept-resistant graft rejection was allocated to elevated pretransplant frequencies of CD28 memory T cells. Owing to different requirements in CD28 costimulatory and CTLA-4 coinhibitory signals to control naive and memory T cells, selective antagonists of CD28-CD80/86 interactions have been developed on the rationale that preservation of CTLA-4-mediated regulatory mechanisms would result in a better control of alloreactivity and would represent a regulatory T-cell-compatible immunosuppression. After the successful testing of selective CD28 antagonists in First In Human studies, this review delineates how this shift in paradigm performed in preclinical transplantation models and evaluates its clinical potential.

CYP3A5 genotype affects time to therapeutic tacrolimus level in pediatric kidney transplant recipients.

Optimal management of immunosuppression in kidney transplantation requires a delicate balance of efficacy and toxicity. Tacrolimus (TAC) dose requirements are significantly impacted by genetic variation in CYP3A5 polymorphisms, however the impact that genotype has on clinical outcomes in the pediatric kidney transplant population remains unclear. We evaluated a retrospective cohort of 98 pediatric kidney transplant recipients. The primary exposure was CYP3A5 genotype, which classified each recipient into the expresser (at least one CYP3A5*1 allele) or non-expresser group (only CYP3A5*3 alleles). The primary outcome was time to achieve a steady therapeutic TAC concentration. Secondary outcomes include incidence of early allograft rejection and calcineurin inhibitor (CNI) nephrotoxicity during the first year post-transplant. The study cohort included 55 (56%) expressers and 43 (44%) non-expressers of the CYP3A5*1 allele. Expressers had a significantly longer time to achieve a steady therapeutic TAC concentration than non-expressers (log rank, P=0.03). Expressers had a trend for higher incidence of early allograft rejection (29.1% vs 16.3%, log rank, P=0.16). Early biopsy-proven CNI nephrotoxicity was seen in 60% of recipients, with no differences in the rate between expressers and non-expressers. Pediatric kidney transplant recipients with the CYP3A5*1 allele (expressers) take a longer time to achieve therapeutic TAC levels than those with the CYP3A5*3 allele (non-expressers). However, we observed no significant differences in acute rejection or CNI nephrotoxicity based on CYP3A5 genotype. Thus CYP3A5 genotype was not observed to have an immediate impact on early transplant outcomes.

Nonimmunologic Factors Affecting Long-Term Outcomes of Deceased-Donor Kidney Transplant.

We investigated the impact of nonimmuno-logic factors on patient and graft survival after deceased-donor kidney transplant. All deceased-donor kidney transplants performed between January 2004 and December 2015 were included in our analyses. We used the independent t test to calculate significant differences between means above and below medians of various parameters. All study patients (N = 205; 58.7% males) received antithymocyte globulin as induction therapy and standard maintenance therapy. Patients were free from infection, malignancy, and cardiac, liver, and pulmonary system abnormalities. Most patients (89.2%) were recipients of a first graft. Median patient age, weight, and cold ischemia time were 38 years, 65 kg, and 15 hours, respectively. Delayed graft function, diabetes mellitus, and hypertension occurred in 19.1%, 43.4%, and 77.9% of patients, respectively. The 1- and 5-year graft survival rates were 95% and 73.8%. Graft survival was not affected by donor or recipient sex or recipient diabetes or hypertension. However, graft survival was longer in patients who received no graft biopsy (8.2 vs 6.9 y; P = .027) and in those who had diagnosis of calcineurin inhibitor nephrotoxicity versus antibody-mediated rejection after biopsy (8.19 vs 3.66 y; P = .0047). Longer survival was shown with donors who had traumatic death versus cerebro-vascular accident (5.9 vs 5.3 y; P = .029) and donors below the 50th percentile in age (8.23 and 7.14 y; P = .0026) but less with donors who had terminal acute kidney injury (6.97 vs 8.16 y; P = .0062). We found a negative correlation between graft survival and donor age (P = .01) and 1-year serum creatinine (P = .01). Donor age, cause of brain death, and acute kidney injury affected graft survival in our study cohort but not donor or recipient sex or posttransplant or donor blood pressure.

Th1, Th2, Th17 cell subsets in two different immunosuppressive protocols in renal allograft recipients (Sirolimus vs mycophenolate mofetil): A cohort study

Long-term use of calcineurin inhibitors (CNI) is associated with nephrotoxicity, which is an important cause of renal dysfunction. Therefore, CNI-minimization strategies which decrease the CNI nephrotoxicity under the protection of additional immunosuppressant drugs have been developed. The aim of current cohort study was to compare the effect of two immunosuppressive protocols [tacrolimus (TAC) in combination with mycophenolate mofetil (MMF) and prednisolone (PRED) versus TAC in combination with sirolimus (SRL) and prednisolone] on the frequency of T helper cell subsets (Th1, Th2 and Th17 cells) and their associated cytokine (IFN-γ, IL-4 and IL-17A) levels in renal allograft recipients.In this study, renal transplant recipients who received induction therapy (Antithymocyte globulin) and were also on triple immunosuppressive therapy were included and divided in to two groups: Group A was comprised 14 patients who received TAC, MMF and PERD whereas group B was composed of 10 patients who received TAC, SRL and PERD. The frequency of Th1, Th2 and Th17 cells in the peripheral blood mononuclear cells (PBMCs) of the patients was analyzed by flow cytometry before and 4 months after transplantation. In addition, IFN-γ, IL-4 and IL-17A concentrations in PBMC culture supernatants of patients before and 4 months after transplantation were quantified by ELISA.The results of our study showed that TAC, MMF and PRED protocol did not diminish the frequency of Th17 cells at 4 months post-transplantation (5% ± 2.5) compared with pre-transplantation (2.3% ± 1; P < 0.05). However, Th17 (3.6% ± 1.5 pre-transplantation vs 2.2% ± 0.9 at 4 months post-transplantation; P < 0.05), Th2 (1.4% ± 0.3 pre-transplantation vs 0.8% ± 0.4 at 4 months post-transplantation; P < 0.05) cell subsets and IL-4 concentration (71.5 pg/ml ± 12 pre-transplantation vs 62.5 pg/ml ±4.4 at 4 months post-transplantation; P < 0.05) were significantly decreased after transplantation in patients who had received SRL, TAC and PRED.In conclusion, the data of the current study suggest that using reduced dose of TAC in SRL, TAC and PRED protocol is in favor of allograft survival; however a cohort study with larger sample size is needed for confirming our results.

MTOR inhibitors in pediatric liver transplant recipients

During the past decade, mTOR inhibitors (mTORi), everolimus and sirolimus, have been increasingly used after adult liver transplantation (LT). The aim of the present study was to describe the use of mTORi in pediatric LT recipients. All pediatric LT recipients who received mTORi before December 2017 from 4 European pediatric LT centers were included and analyzed. The present retrospective study included 30 patients; 21 were male (70%), median age was 9.3 years (range: 1.2-17.1 years) at mTORi introduction. Main indications for mTORi introduction were pre-existing liver malignancy (43.3%), calcineurin inhibitor (CNI) nephrotoxicity (26.7%), or rejection (23.4%). At last follow-up, mTORi CNIs were withdrawn in 10 patients (10/29, 34.5%). The median dose of mTORi was 1.8 mg/day (range: 0.3-5.0) or 0.058 mg/kg/day (range: 0.01-0.26), and the median trough level was 5.1 μg/L (range: 1.0-15.5). After a median follow-up of 2.8 years (range: 0.2-10.0), 50.0% of the patients presented with at least one adverse event. The main adverse events included hyperlipidemia, proteinuria, dermatitis, and mucitis. Overall mTORi discontinuation rate was 23.3% (10.0% because of adverse event). Introduction of mTORi had no significant impact on renal function. Our results suggest that mTORi can be used in pediatric LT recipients in different clinical situations, both to reinforce immunosuppressive therapy, and to reduce CNI and related toxicity.

Introduction of everolimus in kidney transplant recipients at a late posttransplant stage.

This minireview focuses on the current knowledge about the introduction of everolimus (EVL), a mammalian target of rapamycin inhibitor, with calcineurin inhibitor (CNI) elimination or minimization in kidney transplant recipients at a late posttransplant stage. Within, we have summarized two major clinical trials, ASCERTAIN and APOLLO, and seven other retrospective or nonrandomized studies. In the open-label multicenter ASCERTAIN study, the estimated glomerular filtration rate (eGFR) at 24 mo after conversion was not significantly different between three groups-EVL with CNI elimination, CNI minimization and continued CNI unchanged-at a mean of 5.4 years after transplantation. However, recipients with baseline creatinine clearance higher than 50 mL/min had a greater increase in measured GFR after CNI elimination. In the open-label multicenter APOLLO study, adjusted eGFR within the on-treatment population was significantly higher in the EVL continuation group than in the CNI continuation group at 12 mo after conversion at a mean of 7 years posttransplantation. Other studies on recipients without adverse events and already having satisfactory renal function showed favorable graft function by EVL late-induction with CNI elimination or reduction. These studies showed that chronic allograft nephropathy, CNI nephrotoxicity, CNI arteriolopathy, cancer and viral infection (especially cytomegalovirus infection) may be good indications for late conversion to EVL.

Approaches to correction of immunosuppressive therapy in chronic nephrotoxicity of calcineurin inhibitors

Approaches to correction of immunosuppressive therapy in chronic nephrotoxicity of calcineurin inhibitors

Identifying the Specific Causes of Kidney Allograft Loss

Understanding the specific causes of kidney allograft loss is mandatory to improve the longevity of kidney allografts. However, the current literature is limited by the low level of phenotyping, small series with selected populations or data from registries that lack precision diagnoses. We conducted a multicentric prospective study including unselected kidney transplant recipients from 4 referral centers transplanted between January 2004 and 2014. Donor and recipient transplant parameters, clinical and biological post transplant parameters as well as circulating anti-HLA DSA and allograft biopsies performed post transplant (protocol and for causes) were included. The main outcome measure was long-term kidney allograft survival and specific causes of allograft loss. Main analyzes comprised 4,921 kidney recipients. A total of 10,293 kidney allograft biopsies were analyzed (4778 protocol biopsies and 5515 for cause biopsies). During a median follow-up post transplant of 6.52 years, 929 graft losses occurred. After inclusion of biopsy, clinical, biological, and anti HLA DSA data, a primary cause was identified in 96% of cases. The causes of loss were: immune related (32% of antibody-mediated rejection, 4.5% of T-cell mediated rejection), surgical related (21% of thrombosis, 2.5% of urinary disease), medical related (tumoral, infectious or cardiac intercurrent disease (20%), recurrence of primary disease (7.5%), virus related (BK or CMV associated nephropathy, 5.5%) and calcineurin inhibitor nephrotoxicity (1.5%). After exclusion of primary non-function and early vascular and urological complications, antibody-mediated rejection was the leading diagnosis for allograft failures (40%). Antibody-mediated rejection was associated with the worse allograft survival (55% at 9 years). Conditional probability plot of allograft diagnoses give the dynamic range of allograft injuries with time (figure 1).In this multicentric extensively phenotyped population of kidney transplant recipients, we identify the contemporary picture of specific causes of kidney graft loss. Such effort highlights the current priorities to detect such complications to improve long-term allograft outcomes.